Wegovy and Progesterone HRT Interaction: What Patients and Clinicians Need to Know

The short answer

The Wegovy label's caution is about oral medicines in general: semaglutide delays gastric emptying and may affect their absorption, and the label advises monitoring [1]. The Prometrium label's relevant warning is about the capsules themselves, transient dizziness and drowsiness, with a bedtime dose [3]. Neither label names the other drug [1][2].

Two drugs, two different clearance routes

Wegovy is semaglutide, a GLP-1 receptor agonist with 94% sequence homology to human GLP-1 that delays gastric emptying [1]. Its label states that semaglutide is broken down by proteolytic cleavage of the peptide backbone and beta-oxidation of its fatty acid side chain rather than by CYP enzymes, and that it has very low potential to inhibit or induce CYP enzymes [1].

Prometrium is oral micronized progesterone. Its label says progesterone is metabolized primarily by the liver, largely to pregnanediols and pregnanolones, which are conjugated and excreted in bile and urine [2]. The label does not name the enzyme responsible for most of that metabolism. CYP3A4 appears once, in a Clinical Pharmacology note that ketoconazole inhibited progesterone metabolism in human liver microsomes, followed by the statement that the clinical relevance of the in-vitro finding is unknown [2].

What the Wegovy label says about oral medicines

The label says Wegovy causes a delay of gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. It advises monitoring the effects of oral medicines taken with Wegovy and considering increased clinical or laboratory monitoring for drugs with a narrow therapeutic index or that require clinical monitoring [1].

The same section states that in clinical pharmacology trials with semaglutide 1 mg once weekly injection, semaglutide did not affect the absorption of orally administered medications [1]. The label reports no clinically significant effect on lisinopril, warfarin, metformin, digoxin, ethinyl estradiol, levonorgestrel, furosemide or rosuvastatin, and omeprazole did not change semaglutide levels. With the tablet form, levothyroxine total exposure rose 33% [1]. Progesterone is not on that list, so the label gives no measurement of Wegovy's effect on oral progesterone absorption [1].

What the Prometrium label covers

Prometrium (progesterone USP) 100 mg and 200 mg capsules are approved for two things only: prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving conjugated estrogens tablets, and secondary amenorrhea [3]. The endometrial-protection dose is 200 mg orally at bedtime for 12 days sequentially per 28-day cycle; secondary amenorrhea is treated with 400 mg at bedtime for 10 days [3].

Two details matter on a page about this pairing. First, the label's endometrial data and dosing are built around conjugated estrogens, not estradiol, so a progesterone-plus-estradiol regimen is not the labeled combination [3]. Second, the label has no separate drug-interactions section and does not name semaglutide, GLP-1 receptor agonists or CYP3A4 inducers [2].

Absorption details from the label: maximum serum concentrations are reached within 3 hours of an oral dose, and food increased progesterone bioavailability relative to fasting in a study using the 200 mg dose [2].

The current label, revision 02/2026, has no boxed warning. Prometrium was among the products whose updated labeling FDA approved on 12 February 2026, with the cardiovascular, breast cancer and probable dementia boxed-warning language removed [4][5][2].

Dizziness and drowsiness appear on the Prometrium label

The Prometrium label says the capsules may cause transient dizziness and drowsiness, should be used with caution when driving a motor vehicle or operating machinery, and should be taken as a single daily dose at bedtime [3]. During initial therapy a few women have had extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk and shortness of breath [2]. In the label's 3-year trial of cyclic Prometrium 200 mg plus conjugated estrogens, dizziness was reported by 15% versus 9% on placebo; the placebo group took no hormones, so that figure cannot separate progesterone from estrogen [2].

In Wegovy's pooled weight-management trials, 2,116 adults on 2.4 mg weekly were compared with 1,261 on placebo for up to 68 weeks: dizziness 8% versus 4%, fatigue 11% versus 5%, headache 14% versus 10% [1]. Dizziness is therefore listed on both labels, from different trials in different populations.

Timing rules written into the labels

Prometrium is a single daily dose at bedtime [3]. Wegovy injection is given once weekly, at any time of day, with or without meals [1]. Wegovy tablets are taken in the morning on an empty stomach with up to 4 ounces of water, and the label directs waiting at least 30 minutes before food, drink or other oral medicines [1].

Safety information the labels carry

Prometrium is contraindicated in peanut allergy (the capsules contain peanut oil), undiagnosed abnormal genital bleeding, known or suspected breast cancer or a history of it, active or prior deep vein thrombosis or pulmonary embolism, active or prior arterial thromboembolic disease, and known liver disease [3]. The label directs stopping immediately if a PE, DVT, stroke or MI occurs or is suspected, and if feasible at least 4 to 6 weeks before surgery associated with increased clot risk or during prolonged immobilization [2]. It also says progesterone may cause some degree of fluid retention, and that women with cardiac or renal dysfunction warrant careful observation [3].

Wegovy's label directs discontinuing the drug if pancreatitis is suspected, and reports gallbladder disease more often than placebo (cholelithiasis 1.6% versus 0.7%) and severe gastrointestinal reactions in 4.1% versus 0.9% [1].